This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. These are highly translational studies in which we have observed that the underlying basis of mutational disease is frequently the mis-routing of otherwise functional proteins, in this case a receptor[unreadable]but other labs have now confirmed this for other receptors, ion channels and enzymes. We have shown that these mutant receptors can be rescued and restored to function by pharmacological chaperones. We have determined that the regulation of routing is also a normal type of post-translational regulation that occurs in routine cell function and can be controlled. During the prior period we have shown that misfolded hGnRHR can be refolded so that therapeutic agents need not be continuously present. We have also shown that control of hGnRHR helps explain the basics of the ability of this receptor to respond to both amplitude and frequency modulated signals. GnRHR analogs were screened for potential therapeutic action and a review was published.